The cloning and characterization of leukemia oncoproteins over the last 25 years has resulted in a greater understanding of the central role of transcription factors in hematopoiesis and leukemogenesis. Human acute myeloid leukemias are characterized by the presence of chromosomal translocations, which, result in the fusion of coding sequences from one gene to coding sequences of transcription factors. Overexpression of these fusion transcription factors often inhibits myeloid differentiation and such fusion transcription factors may play an important role in the development of the leukemic phenotype. Though much is known about the expression of human transcription-factor oncoproteins in clinical disease, their transcriptional targets are not as clear. Growth factor independence-1 (GFI1) is a transcription factor that is essential for normal lymphoid and myeloid development. GFI1 was originally identified as a frequent target of Moloney murine leukemia virus insertion in rat and mouse genomes. Transgenic expression of GFI1 is oncogenic and potently accelerates leukemogenesis induced by the Moloney murine leukemia virus; confirming the role of GFI1 in Moloney oncogenesis. Mutation of GFl1 leads to a human neutropenia syndrome that predisposes to acute myeloid leukemia. Our preliminary evidence indicates that GFl1 is targeted by a chimeric transcription factor found in human acute myeloid leukemia, and that GFI1 targets key myeloid lineage transcription factors. We hypothesize that GFI1 tethers a multiprotein transcription complex to DNA to control the expression of lineage-specific transcription factors, and that abnormal GFl1 expression predisposes to acute myeloid leukemia. We will molecularly characterize GFI1 target genes in myelopoiesis, and biologically test suggested genetic interactions. Moreover, we will dissect GFl1 as a target of a human chimeric transcription factor oncoprotein, and determine whether loss of GFl1 is predisposing to leukemia.